Elucidation of the early molecular events associated with human immunodeficiency virus type 1 (HIV-1) infection is of major importance to AIDS therapeutics and vaccine development. Although cell surface CD4 is the primary receptor for HIV-1, evidence suggests that other cell surface molecules, either independently or in association with CD4, may participate in virus binding and entry. We have shown that cell surface heparan sulfate (HS) proteoglycans participate in the infection of CD4+ T- cell lines. Removal of HS from the cell surface by specific enzyme digestion or the reduction of the sulfation of HS chains by a metabolic competitor reduced virus binding and infection. The data also supported that both HS and CD4 receptor participate in either initial virus attachment or postbinding events, and that the V3 domain of an HIV-1 envelope protein, gp120, interacts with cell surface HS proteoglycans. Topics of current interest include (1) analysis of molecular interactions between HIV-1 envelope proteins and cell surface HS proteoglycans, and (2) biochemical characterization of HS proteoglycans in HIV-1 target T- lymphocytes.